Influenza virus of type A (IAV) causes acute respiratory infections that are highly contagious and afflict humans and animals with significant morbidity and mortality.
Activation of host innate immune system aims at controlling the spreading and deleterious effects of IAV infection. However, excessive inflammatory response, due to a dysregulation of cytokine release and strong recruitment of neutrophils at the site of infection, may also mediate severe lung inflammation and increased pathogenesis of IAV. Cytokine dysregulation during IAV infection is thus often associated with fatal outcome of IAV.
The sites of virus replication in the respiratory tract represent complex microenvironments, in which extracellular proteases are present in large amounts. Some of these proteases (trypsin, tryptase) can play a role both in virus replication and innate immune responses as they are important mediators of inflammatory processes through the activation of a family of receptors called Protease-Activated Receptors (PARs).
To date four PARs, activated by different proteases, have been cloned (PAR1-4). After cleavage of the receptor by proteases, the newly released amino-terminal sequence binds and activates internally the receptor. A role for one member of this family, PAR2, in lung inflammatory processes has been investigated in several studies. On one hand, PAR2 activation by selective agonists in the lung, induces signs of inflammation (recruitment of inflammatory cells, cytokine and chemokine release and endogenous activation of PAR2 promotes allergic sensitization and the recruitment of inflammatory cells to the airways. On the other hand, PAR2 agonists inhibit LPS-induced granulocyte recruitment, and PAR2-deficient mice displayed more severe lung inflammation in a model of bacterial (Pseudomonas aeruginosa) infection.
Therefore, the exact role of PAR2 in lung inflammatory response is unclear. Particularly, in the context of viral infection, the role of PAR2 activation still has to be investigated. Elevated PAR levels (including PAR2) have been observed in the airways of IAV-infected mice (Lan R S. et al. 2004), suggesting a role for this receptor in the pathogenesis of viral disease. More recently, an in vitro study has shown that PAR2 activation on monocytes enhanced the suppressive effects of IFN-γ on IAV replication (Feld M. et al. 2008). The role for PAR2 activation on other cell types, and particularly in epithelial cells, one of the primary cell type exposed to different pathogens and to IAV has never been studied in the context of viral infection. Further, the specific role for PAR2 activation in vivo in models of viral infection has never been addressed.